You need to get calories from somewhere, should it be from carbohydrate or fat?

Thursday, November 10, 2011

LIRKO mice (3) The MCQ

**************EDIT - This is serious**************

It has been pointed out that this post is a deliberate intention to mislead. I would like to deny this categorically. The allegation is based around my personal error relating to the renal glycosuria threshold of rats. I have never treated a rat for diabetes. Apparently they do not become glycosuric until blood glucose exceeds around 400mg/dl, somewhat above the glycaemic level of LIRKO mice and waaaay above the cat, dog or human threshold.

They are still functionally diabetic, despite the lack of glycosuria, in terms of hyperglycaemia. But it appears that YOU CANNOT MAKE JAM from their urine.

I would really like to say I hope Dr Guyenet did not waste too much time trying to get his rather watery jam to set. But I just can't. I guess he spent a lot of hours.

******************END EDIT******************
I see the LIRKO mouse has resurfaced as a destructor of the role of insulin in obesity yet again. I've posted on the LIRKO mouse in the past so this little quizz should be quite straight forward. I skipped the questions about leptin because I felt like it.

WARNING some of the questions may have more than one correct answer.

Q1. What is the blood glucose of a LIRKO mouse after a mouthfull of chow?
a. 400mg/dl
b. 400mg/dl
c. 400mg/dl
d. WTF, no one told me LIRKO mice are intensely diabetic.

Q2. What is the urine glucose concentration of a LIRKO mouse?
a. Some
b. Quite a lot
c. More than quite a lot
d. Obesity researchers boil it down to make jam.

Q3. The liver of a LIRKO mouse has no access to glucose. Where does it source it's energy?
a. Not from glucose
b. Definitely not from glucose
c. Absolutely, definitely not from glucose
d. Where's the fat?

Q4. How much fat is there in mouse diet F9?
a. Not a lot.
b. Not a lot
e. Not a lot
d. 10%, just about enough to run the liver on, rather badly, giving early onset cirrhosis and death.

Q5. How much de novo lipogenesis (DNL) from glucose is done in the liver of a LIRKO mouse?
a. None
b. Zero
c. Zilch
d. LIRKO mouse liver can't take up glucose for anything because it has no insulin receptors. Ha ha, gotcha, this is a trick question.

Q6. If the dietary fat is used to run the liver and there is no DNL, where does the fat in adipose tissue fat come from?
a. Thin air.
b. Spontaneous generation
c. Beamed in from The Enterprise
d. A small nuclear reactor
e. It doesn't, you can't put in what you haven't got. OK, there is a smidge of DNL in adipocytes.

Q7. If a LIRKO mouse at the gym is losing more calories down the urinals (where glucose is collected for making jam) than it burns on the treadmill, why doesn't it eat more?
a. Blood glucose is 400mg/dl
b. Blood insulin is 80ng/ml
c. Both.
d. Yeugh, is that really how they make jam?

Q8. The LIRKO mouse is hyperinsulinaemic. By how much does this lower plasma free fatty acids?
a. By 40%
b. By 40%
c. By 40%
d. By only 40% because adipocytes, like the rest of the mouse, are intensely insulin resistant.
e. WTF, no one told me they had depressed FFAs.

Q9. How would the LIRKO mouse cope with a saturated fat based, intensely ketogenic diet?
a. Well
b. Really well
c. Really, really well
d. Don't ask, don't even think about it.

Q10. Obesity researchers trot out the LIRKO mouse because:
a. They want to share
b. They want to share
c. They want to share
d. Shut up and eat your carbohydrate. You need insulin to get slim. Mmmm LIRKO jam...

Why even use genetically modified mice to test the Carbohydrate Insulin Hypothesis? Why not use normal, healthy, unadulterated mice? Allow them all to feed ad-libitum on the mice-equivalent of the SAD or Western diet -- plenty of sugar, refined starches and "healthy whole grains" -- then inject half of the study with insulin to simulate chronically raised circulating insulin levels. Sit back and record any increased fat mass.

im still waiting for dat insulin fairies to make me fat and sick. maybe is all the fat @ protein i eat? hey peter i asked Paul Jaminet the other day about my 57 mg/dl fasting blood sugar(10 hrs after eating) and he implied it was dat hi protein @ insulin so i said "but dsnt the pancreas stops secreting insulin when glucose levels drop below 83 mg/dL so my insulin levels should be kite low amayrigth?" and he just said la la la la "I don’t know why your blood glucose is low!" :/

so what do you think, hi, low? mr food reward says dat insulin is good but im not so sure...

Will testing my glucose in the morning then comparing it after drinking my usual 2 splenda diet cokes will reveal anything useful?

Are there any reliable studies that show artificial sweetners causing insulin spikes? Having stalled at 205 with even a 48 hour liquid fast producing nothing but a nice buzz but no weight loss I am trying to understand why I cannot get down to what the Gov says I should weigh for my height...6 foot 185lb...have gone from 240 to currect 205.

No, you can't do this. The insulin drops blood glucose to a level of "eat or die", never mind what it does to lipolysis. The effect is then that of hypoglycaemia. The LIRKO mouse is special. It is ONLY hyperinsulinaemic because it is hyperglycaemic. No hypoglycaemic drive to eat. A bit like I used to be 60 minutes after a huge bowl of brown rice or whole meal pasta with chickpeas. Not hungry. Dread to think what either insulin or glucose were... But I wasn't hungry, just asleep. a better comparison is a normal human type 2 diabetic starting low dose insulin with a massive carb diet. HbA1c may be 10%, ie no hypos, but they will still gain a stone on starting insulin. It's routine.

Tim,

Why should he? The LIRKO mouse is hyperinsulinaemic and slim. case closed.You, me and the rest of the world don't need to worry our silly little heads about why.

Pierre,

It's hard to say what your fasting insulin might be. It depends where your metabolism has been. Post obese people can have a 3 days of fasting insulin of 20microIU/ml w/o splenda. A non post obese person would be down at 2microIU/ml... The anecdote through comments suggests possibly years to normalise fasting insulin. Certainly 6 weeks of water fasting won't do it acutely...

Pablo,

Your fasting insulin will be low, you are insulin sensitive. Whatever else you do, you have lots of mitochondria. I guess they work pretty well.

And I agree with blogblog. I am not a mouse. I did not evolve on grain. I am a monkey, perhaps some form of mutant chimpanzee.

As a result, I appear to have evolved to eat mainly leafy greens, some starchy fruits, some rare sweet fruits, and whatever red colobus monkeys I can catch and tear limb from limb. Sorry about that. If I can't find any red colobus monkeys, I'll make do with beef.

But luckily I have a back-up system that lets me live on those starchy stuffs if I have to so I can avoid extinction. I love evolution. Please pass the red colobus monkey haunch. (Note: will have sex for red colobus monkey haunch! q.v. http://www.msnbc.msn.com/id/30108925/ns/technology_and_science-science/t/lady-chimps-will-mate-meat/#.Try8GlZSlGM)

I've just read about a product called plumpy'nut which is designed to quickly fatten severely malnourished children at minimal cost. 500Cal in every 92g pouch. The magical ingredients are peanut paste, milk powder and sugar (plus a few vitamins and minerals). SAD in a convenient longlife pouch!

It kind of amazes me, a phd studying the neurobiology of obesity cannot seem to come to this conclusion independently: in order for insulin to exert physiological effects, functional receptors on the cell surface must be present.

It's shocking that random people on the interweb who are NOT recent grads studying obesity, must then come along and point this out.

Even more shocking is that the discussion thread has comments like this in it:

"A theory of obesity that can't explain how healthy people become obese is not a very good theory of obesity." (WHY MUST A THEORY OF OBESITY EXTEND TO EVERY SINGLE PERSON, WHEN CLEARLY EVIDENCE SUGGESTS MOST PEOPLE ARE OBESITY RESISTANT AND STOP GAINING FAT AFTER A FEW POUNDS? Why would you assume everyone should develop obesity? This is like assuming everyone will develop lung cancer after having a smoking addiction. The fact many people smoke 80 years and never develop cancer does not mean cigarettes are not carcinogenic.)

and also:"FrankG said...

Dr Robert Lustig still seems convinced about the relationship between chronically raised insulin and obesity..."

(Has it been disproven yet? Last time I checked, people who matter much more than Stephan G and random internet commenter generally agree insulin leads to fat gain. Might you want to consider taking some science classes, oh and bring Stephan G. with you he could use them. Real medical doctors expect body fat gain after initiating insulin therapy in a diabetic person.)

Even more shocking than Stephans arguments is that a single commenter points it out how medically false it is to try to argue that insulin does not control fat storage. I have to rant in private on my blog, or come to hyperlipid just to make sure I am not going koo koo: it's actually everyone else who refuses to acknowledge scientific facts.

Stephan Guyenet and others who would completely ignore scientific fact:

If insulin does not lead to fat storage, why do people who develop random neoplasia of insulin producing cells often become obese, sometimes morbidly obese? These people are totally normal metabolically, until one day their insulin levels went to 800 gazillion, and all of a sudden, ruh roh, fat as a house. Some have elected for bariatric surgeries only to find out they actually had an insulinoma. Woops.

Also: If everyone should be capable of developing obesity, why do some individuals resist fat gain in spite of insulinoma and hunger? If it is as simple as food intake and high insulin, all people with insulinomas should become equally obese, but some gain no weight at all. This suggests obesity is specific and genetic , requires insulin, but insulin is not sufficient, as genetics of adipocytes (to make fat in the presence of insulin) and other factors are ultimately deciding.

If insulin is not required for fat storage, why are infants with donahue syndrome, born with a genetic defect in the insulin receptor so that it has <15% functionality, have very strikingly emaciated adipose tissue, not dissimilar to these severely IR LIRKO mice? Answer: because insulin IS required for fat storage, so having an adipocyte with insulin receptors functioning at <15% of normal will result in being extremely emaciated.

uh-oh -- Stephan has a new article out that says 1) insulin drives "nutrients" into cells as its primary function, 2) "energy excess" causes insulin resistance, and 3) people lie about their energy intake, especially middle-aged women. it's back to the old litany! ...i noticed that only his syncophants left any comments.

Though I agree with you in general, I'm going to guess the insulinoma point would be argued in the the same way as injections: the insulin by itself causes a needed increase in food/blood glucose, whereas in a normal circumstance, carbs are consumed, and the insulin is the reaction. But since insulin secretion inhibition does the reverse [discourage fat gain] too, I think the evidence is strong.

pyker,

Damn, that's an all time great!

tess,

I hardly want to even read it. Stephan has been a favorite blogger of mine for so long, but it seems he's now much more concerned with his reputation and "mentor" than with pursuing and providing information for the sake of curiosity and genuine interest. For the last several posts, I've kept thinking he's going to finally reveal the connecting and coherent explanation and evidence for which I've been waiting, but I've been continually disappointed.

Stephan has been a favorite blogger of mine for so long, but it seems he's now much more concerned with his reputation and "mentor" than with pursuing and providing information for the sake of curiosity and genuine interest. For the last several posts, I've kept thinking he's going to finally reveal the connecting and coherent explanation and evidence for which I've been waiting, but I've been continually disappointed.

First point: I like and read this blog. I also like and read Stephan's blog. I'm still agnostic about many nutritional points and I enjoy both blogs, like many paleo lurkers.

Second point: I really enjoy the claims that Stephan's blog is filled with "sycophants" when his blog comments have a lot more dissenting arguments than this one.

Many commenters here raise good points, as do many on Stephan's blog, but it's more fun when the actual arguments take center stage instead of the people putting them forward. This is supposed to be science, not pro wrestling.

pyker, do you mean palatability or reward? LMAO. As john says "Damn, that's an all time great!"

Stan, well I knew I was doing something wrong! But there are plus sides to Stephanwatching. When you see the typical end-product, Hunter's group in Belfast comes to mind or Susan Jebb in the UK, you always wonder whether they were always how they are today or whether there had been a time when they were more sentient. Watching the changes in Stephan I feel privileged. It feels comparable to being "on shift" when the first pulsar, LGM-1, was discovered by Bell and Hewish... Of course you still are left wondering at the reasons for the shift from sentience to current state.

Adam, you may have noticed that I never really get chance to take part in the discussions in comments, it's probably a toddler associated syndrome! I don't really have a need to convince people, I'm interested in how physiology works and I see no real use in Stephan's ideas. Equally I have zero interest in convincing him, or any who agrees with him, that he is incorrect. That's their problem. I only engaged in the Taubes bashing debacle because a) I largely agree with Taubes b) Stephan's critique was so awful I had to point out the awful economies with the physiology cited. He does seem like a proto-Hunter. Whether his ideas, ignoring 3rd rate bashing of Taubes, hold water does not really interest me. I have to say it must be very difficult to be wrong about everything and so it is even conceivable that he is correct in some aspects, who knows... Like John I used to read Stephan. Nowadays I don't see the point.

Next time you'd like to get something off your chest that was inspired by "not" reading something you obviously read, simply write it down on a sheet of paper and toss it away. This way, you'll say what you need to, and the rest of us won't see you as a hypocrite.

Peter, that email I sent you on Stephan's insulin resistance post has now been forwarded to Stephan himself. Here is the email in case your readers are interested.

Stephan says:

'I read an interesting paper in 2009 titled "Insulin Resistance is an Antioxidant Defense Mechanism" (1). The authors presented compelling evidence that exposure to excess nutrients causes cells to produce excess reactive oxygen species, which in turn shuts down insulin signaling. This was presumably due to the fact that the mitochondria, the cells' tiny furnaces, were overloaded with energy.'

In fact the message of this paper is that insulin resistance is caused at least partly by manganese deficiency. Calling it energy overload misses the point. The cells are not deliberately producing ROS to protect themselves against energy overload. They produce ROS in an oscillatory fashion for signalling purposes, and their mitochondria oscillate too. The cells oscillate between insulin sensitivity and insulin resistance, and insulin resistance is what you get if you abolish oscillatory insulin secretion.

Stephan again:

'Then there is the idea that mitochondrial dysfunction causes obesity. Now, we have entered into the realm of pure speculation.'

Obese people have calcium overload in their adipocytes. This is not speculation. Calcium overload means malfunctioning mitochondria. Mitochondrial calcium normally oscillates, and so does lipolysis, which is inhibited by calcium.

Magnesium-ATP pumps the calcium out of the cell or into the endoplasmic reticulum where it can't harm the mitochondria or inhibit lipolysis. Obese people have been found to have a low magnesium intake.

Hi Jane, just getting time to catch up. I would agree that insulin controls many many more things than lipolysis and glucose uptake. Mg undoubtedly and I am quite willing to believe Mn too. And probably Zn and chromium. I have long wondered about exactly WHY insulin controls K+ uptake. Much of this probably comes back to insulin and cells becoming metabolically active. I have no doubt what so ever that free radicals are crucial signalling molecules. I think there is a world of difference between free radicals produced by fructose metabolism in the cytoplasm and those produced at complex 1 during beta oxidation. They probably send differing messages and have differing outcomes. One of the most interesting things about the twins papers was that the obese twin(s) not only had markedly reduced mitochondrial DNA in their adipocytes but also that the control NFs for mitochondrial biogenesis were also downregulated. If we had cells crying out for mitochondria I would expect peroxisome proliferator–activated receptor γ coactivator 1 to be upregulated, not downregulated. This has me thinking about signalling and free radicals. I'll be looking at the paper and a number of others on cytoplasmic ROS generation as I get the chance. It also needs looking at in the context of more electron transfer chains vs increased uncoupling as methods of decreaseing free radical signalling. Nick Lane has vitamin and (probably more relevant) mineral deficiencies as potentially significant but concentrates more on signaling when deficiency is not present...

Pablo and blogblog, the idea reminded me of the Naked Mole Rat so I didn't poo poo it immediately. It doesn't help me decide what to put on my plate tonight!

Peter, Stephan's second post in the series is about inflammation, and says 'blocking an inflammatory signal prevents the insulin resistance caused by obesity'. There is an important recent paper on why this might be. Very small amounts of inflammatory cytokines can disrupt or even abolish pancreatic beta cell calcium oscillations. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948622/

Beta cell calcium oscillations are the basis for oscillatory insulin secretion, which prevents insulin resistance. This means that the chronic low-grade inflammation seen in obesity could cause insulin resistance by acting on beta cells.

BTW, about cytoplasmic ROS generation. It looks as if things might work like this: mitochondrial superoxide gets converted into hydrogen peroxide by manganese-SOD, and goes to the cytoplasm where it activates the pentose phosphate pathway, producing NADPH which can be used to make more ROS. So mitochondrial ROS oscillations would be linked to cytoplasmic ROS oscillations, which can cause calcium oscillations because oxidation activates Ca channels and inhibits Ca pumps on the endoplasmic reticulum.

About Me

I am Petro Dobromylskyj, always known as Peter. I'm a vet, trained at the RVC, London University. I was fortunate enough to intercalate a BSc degree in physiology in to my veterinary degree. I was even more fortunate to study under Patrick Wall at UCH, who set me on course to become a veterinary anaesthetist, mostly working on acute pain control. That led to the Certificate then Diploma in Veterinary Anaesthesia and enough publications to allow me to enter the European College of Veterinary Anaesthesia and Analgesia as a de facto founding member. Anaesthesia teaches you a lot. Basic science is combined with the occasional need to act rapidly. Wrong decisions can reward you with catastrophe in seconds. Thinking is mandatory.
I stumbled on to nutrition completely by accident. Once you have been taught to think, it's hard to stop. I think about lots of things. These are some of them.

Organisation (or lack of it)!

The "labels" function on this blog has been used to function as an index and I've tended to group similar subjects together by using labels starting with identical text. If they're numbered within a similar label, start with (1). The archive is predominantly to show the posts I've put up in the last month, if people want to keep track of recent goings on. I might change it to the previous week if I ever get to time to put up enough posts in a week to justify it. That seems to be the best I can do within the limits of this blogging software!